The impact of the new WHO Classification of renal cell carcinoma on the diagnosis of hereditary leiomyomatosis and renal cell carcinoma

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is caused by heterozygous germline variants in the fumarate hydratase (FH) gene [1,2]. Inheritance follows an autosomal dominant pattern. Loss of FH confers a predisposition for various benign and malignant neoplasms, including cutaneous leiomyomas, uterine fibroids and FH-deficient renal cell carcinoma [3]. While benign, cutaneous and uterine manifestations have a relevant impact on quality of life and risk for complications [4]. The vast majority of FH-deficient RCC exhibit an aggressive behavior with invasive growth and potential for early metastatic spread [5]. Additionally, pathogenic germline FH variants have been associated with other neoplasms, such as adrenal gland [10] and Leydig cell tumors [28, 29]. The aggressive behavior of FH-deficient RCC challenges nephron-sparing resection strategies, as a wide margin is recommended. Even after early nephrectomy for surgical removal of FH-deficient renal cell carcinomas, there is a relevant risk for distant metastasis as well as the remaining predisposition for de novo primary renal tumors in the other kidney. Active screening is central to HLRCC care since no preventative HLRCC-specific treatment exists. VEGF/EGFR directed treatment regimes, such as Erlotinib/Bevacizumab demonstrate efficacy against HLRCC-associated RCC [6]. This emphasizes the importance of establishing the correct diagnosis in HLRCC early on to guide therapeutic decisions. Morphologic criteria as well as specific immunohistochemical (IHC) staining and molecular genetics allow the identification of FH-deficient RCC. Changes made in the recent 2022 WHO classification impact the diagnosis of HLRCC in multiple ways. This commentary aims to point out this impact and to raise awareness among pathologists as well as clinicians involved in the care of patients with HLRCC.

Publication DOI: https://doi.org/10.1093/ndt/gfaf032
Divisions: College of Health & Life Sciences > Aston Medical School
Additional Information: Copyright © The Author(s) 2025. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Uncontrolled Keywords: fumarate hydratase (FH),hereditary,Hereditary leiomyomatosis and renal cell cancer (HLRCC),immunohistochemistry,pathology,renal cell carcinoma
Publication ISSN: 1460-2385
Last Modified: 07 Mar 2025 11:49
Date Deposited: 07 Mar 2025 11:49
Full Text Link: https://academi ... gfaf032/8026894
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PURE Output Type: Article
Published Date: 2025-02-20
Published Online Date: 2025-02-20
Accepted Date: 2025-02-01
Authors: Degenhardt, Jan
Tolkach, Yuri
Amin, Mahul B.
Mosiello, Giovanni
Baydar, Dilek Ertoy
Gall, Emilie Cornec-Le
DiCola, Jason
Elhag, Dean
Frezza, Christian
Halbritter, Jan
Guillermo, Ignacio Blanco
Jewett, Michael A.S.
Lattouf, Jean-Baptise
Lovitt, Graham
Lundgren, Per-Olof
Maher, Eamonn R.
Mulders, Peter
Shuch, Brian
Hartmann, Arndt
Müller, Roman-Ulrich

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